The past decade has seen a rapid increase in the application of brain stimulation devices to treat a variety of movement disorders, such as Parkinson's disease (PD), and other neuropathologies. Present noninvasive brain stimulation technologies suffer from fundamental limitations and have yet to reach the level of efficacy of invasive methods, such as deep brain stimulation (DBS). Electrosonic Stimulation (ESStim) is an improved noninvasive modality, which offers the potential of more focal and deeper effects. Preliminary studies with this technique have confirmed improved focality and penetration compared to other forms of noninvasive stimulation (e.g., transcranial DC stimulation (tDCS)), which have translated into a greater magnitude and duration of stimulatory effect compared to the other technologies. This application is focused on evaluating the therapeutic impact of ESStim in PD patients. First in Phase I, we will follow 24 PD patients (12 SHAM, 12 active ESStim stimulation) after giving a constant fixed dose of ESStim for 10 days of stimulation, 20 mins/day, over a two-week period. We will assess a battery of electrophysiology, cognitive, and neurological safety markers in the patients including 64 channel EEG, California Computerized Assessment Package, verbal fluency test, n-back working memory test, PD Adverse Effects Questionnaire, and neurological exams. Additionally, we will evaluate the Unified Parkinson's Disease Rating Scale (UPDRS), bradykinesia test, and walking abilities/gait in the PD patients, evaluated over the 2-week period and for at least six weeks following the last stimulation session. Next in Phase II, we will follow 48 PD patients (12 SHAM, 12 active ESStim stimulation, 12 tDCS, and 12 TUS) after giving a constant fixed dose of stimulation for 10 days, 20 mins/day, over a two-week period. We will evaluate these patients with a battery of Motor, Safety, Mechanistic, and Quality of Life (QOL) tests, comparing the efficacy of the tested interventions. In parallel with the PD treatments, field models of the electromagnetic and sonic fields generated in the brain will be developed with MRI based computational models of each patient and correlated with the efficacy measures recorded during and after the treatment sessions to develop dosing models based on the individualized patient data. Overall, we hypothesize that the proposed experiments, computational studies, and technology development will allow us to test the effectiveness of ESStim compared to other noninvasive technologies in PD patients. The results of the proposed work will serve as the basis for a future large-scale multicenter study to further validate the technique and optimize equipment for use in PD therapy. Future developments with this technology and stimulation method could provide a platform for innovative and improved neurological treatments. PUBLIC HEALTH RELEVANCE: Parkinson's Disease (PD) is a debilitating motor disorder with limited treatment options and as the disease progresses it can require invasive surgical procedures to implant brain stimulation devices in patients' brains to treat the disease. Electrosonic Stimulation (ESStim) is a noninvasive neurostimulation method which improves upon current noninvasive technologies with superior focality, targeting control, and penetration, and for the first time offers the possibility of noninvasive deep brain stimulation (i.e. stimulatig deep brain structures without maximally stimulating the surface). This study analyzes stimulation treatments in PD patients, while exploring technology that can impact other neuropathologies that are currently underserved by present noninvasive options.